This invention relates to methods for the efficient production of quinolonecarboxylic acid synthetic antibacterial agents which are expected for applications such as excellent medicaments and agricultural chemicals and to intermediate compounds to be used therein.
Among quinolone synthetic antibacterial agents useful as antibacterial agents, 5-amino-8-methylquinolonecarboxylic acid derivatives are known to have excellent characteristics. As shown below, 
synthesis of such quinolone derivatives is carried out by allowing a compound of formula (1) to react with a basic substituent compound (Rxe2x80x94H; which means a compound capable of introducing a basic substituent by a substitution reaction). For example, a method of the following formula: 
is known, in which a 5-amino-8-methylquinolonecarboxylic acid BF2 chelate [a compound of the formula (1) wherein R3=NH2, R4=Me and Y=BF2] is allowed to react with a basic substituent compound in an appropriate solvent in the presence of an appropriate base.
That is, a method in which (S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (or its hydrochloride) is allowed to undergo the reaction at 30xc2x0 C. for 3 to 4 days in dimethyl sulfoxide in the presence of N,N-diisopropylamine and then purified, and the thus obtained crystals are allowed to undergo the reaction by heating in a mixed solvent of methanol-1,2-dichloroethane in the presence of triethylamine and then purified, thereby obtaining 5-amino-7-[(S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (JP-A-7-309864 and JP-A-8-198819; the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d) However, this is not an industrially satisfactory method because of the low product yield of approximately from 10 to 30%.
Also known is a method in which 5-amino-8-methylquinolonecarboxylic acid [a compound of the formula (1) wherein R3=NH2, R4=Me and Y=H] and a basic substituent compound are heated in an appropriate solvent in the presence of an appropriate base. That is, a method in which they are stirred and heated at about 100xc2x0 C. for 87 hours in dimethyl sulfoxide in the presence of triethylamine and then treated, and the thus obtained crystals are purified after carrying out deprotection of amino group in the usual way, thereby obtaining 5-amino-7-[(3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl]-1-cyclo propyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (JP-A-8-259561) (the following formula): 
or a method (the following formula): 
in which 5-amino-7-[(S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid is obtained (Chem. Pharm. Bull., 44, 1376 (1996)).
However, yields of the final products by these methods are still low, namely 38% and 56% respectively, so that, though the yields are slightly improved in comparison with the foregoing method, they are not industrially satisfactory methods.
Thus, the previous methods for the production of 5-amino-8-methylquinolonecarboxylic acid derivatives were not satisfactory as an industrial production method.
Under such a situation, the present inventors have examined the reason of low yield of the previous reaction of a boron chelate compound of Y=xe2x80x94B(R5)2 in the compound of formula (1) of the invention [(5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid-O3,O4)difluoroboron] with a basic substituent compound.
As a result, it was found that the boron chelate compound easily causes de-chelation on heating. Thus, it was confirmed that de-chelation in the boron chelate quinolone compound preferentially proceeds rather than reacting with a basic substituent compound when the reaction temperature is increased for the purpose of accelerating the reaction (e.g., even by a heating at 30 to 40xc2x0 C.), while substitution reaction of the compound formed by this de-chelation with the basic substituent compound hardly proceeds at this temperature.
In addition, an open system reaction is carried out under a high temperature (110xc2x0 C.) condition in the case of the substitution reaction of a carboxylic acid type quinolone compound [a compound in which the 3-position carboxyl group is not modified, such as 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid itself] with a pyrrolidine derivative. It was found that, since decomposition reaction of the carboxylic acid quinolone compound itself competitively occurs simultaneously with the substitution reaction by this method, the reaction becomes complex in addition to coloring of the reaction solution. That is, the inventors have considered that yield of the substitution product is reduced due to decomposition of the material compound, and further reduction of the yield occurs because of the difficulty in purifying the final product of interest due to the complex reaction and coloring.
By the way, it is known that the substitution reaction of aromatic halogen compounds with amines sharply progresses when the reaction is carried out in an appropriate solvent under a super-high pressure (cf. Heterocycles, 27,319 (1988); Chem. Lett., 1187 (1987); Synthesis, 1147 (1990); Tetrahedron Lett., 3923 (1990); Bull. Chem. Soc. Jpn., 64, 42 (1991)). However, such a substitution reaction under a high pressure is mainly a reaction with a monocyclic halogen compound such as benzene, pyrimidine, pyrazine or thiazole, and only a few examples such as benzoxazole and benzothiazole are known as bicyclic halogen compounds but there are no reports on 4-quinolone compounds.
An object of the invention is to provide a method for the efficient production of quinolone compounds having excellent antibacterial activity, pharmacokinetics and safety, particularly a 7-substituted 5-amino-8-methylquinolonecarboxylic acid derivative.
As a result of intensive studies, the present inventors have found that a 5-amino-8-methylquinolonecarboxylic acid derivative can be efficiently provided through inhibition of the decomposition reaction of the quinolone material compound, by carrying out the substitution reaction of a 5-amino-1-substituted-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid with a basic substituent compound under a high pressure, thereby accomplishing the invention.
The inventors have further found that the substitution reaction with a basic substituent compound quickly proceeds in-the case of a compound in which the 5-position amino group is acylated, and excellent effects are exerted particularly by the reaction under a pressurized condition, thus resulting in the accomplishment of the invention.
Accordingly, the invention relates to a method for producing a compound represented by formula (2): 
(wherein R1, R2, R3, R4, R, X1 and Y are as defined in the following) which comprises allowing a compound represented by formula (1): 
[wherein R1 represents an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxy group having from 1 to 6 carbon atoms or an alkylamino group having from 1 to 6 carbon atoms,
R2 represents a hydrogen atom or an alkylthio group having from 1 to 6 carbon atoms,
wherein R2 and R1 may be combined to form a cyclic structure together with the carbon atom and nitrogen atom, to which they are bonded, and this ring may contain a sulfur atom as a constituting atom and may further have an alkyl group having from 1 to 6 carbon atoms as a substituent,
R3 represents a hydrogen atom, an amino group, a thiol group, a halogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms,
wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms,
R4 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms,
wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms, and
R4 and R1 maybe combined to form a cyclic structure together with the carbon atom and nitrogen atom, to which they are bonded, and this ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituting atom and may further have an alkyl group having from 1 to 6 carbon atoms as a substituent,
X1 represents a hydrogen atom or a halogen atom,
X2 represents a halogen atom, and
Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidynyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl group having from 2 to 7 carbon atoms, a phenylalkyl group composed of an alkylene group having from 1 to 6 carbon atoms and a phenyl group, or a group of the following formula:
xe2x80x94B(R5)2
(wherein R5 represents a fluorine atom or an acyloxy group having from 2 to 7 carbon atoms)]
to react with a nitrogen-containing basic compound represented by the following formula:
Rxe2x80x94H
(wherein R represents a nitrogen-containing basic substituent in which a nitrogen atom is the binding position), under a pressurized condition in the presence, if necessary, of a base.
The invention also relates to the above production method, wherein the compound of formula (I) is a compound represented by formula (A): 
[wherein X1 is a hydrogen atom or a halogen atom, X2 is a halogen atom, X3 is a hydrogen atom or a halogen atom, R16 is a hydrogen atom or an acyl group, R17 is an acyl group, and R18 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a boron-containing substituent group represented by the following formula:
xe2x80x94B(R5)2
(wherein R5 is a halogen atom or an acyloxy group)].
It also relates to the above production method wherein R5 is a halogen atom or an alkylcarbonyloxy group;
to the above production method wherein R5 is a fluorine atom or an acetyloxy group;
to the above production method wherein the nitrogen-containing basic compound (Rxe2x80x94H) is a compound represented by a formula (B): 
[wherein each of R19 and R20 is independently a hydrogen atom, a lower alkyl group or an amino-substituted cyclopropyl group (this amino group may have a substituent or a protective group), or R19 and R20 may be combined into a group represented by the following formula:
xe2x80x94(CH2)2xe2x80x94
and form a spiro cyclic structure together with the pyrrolidine ring, and R21 is a halogen atom or an amino group which may have a substituent or a protective group];
to the above production method wherein R19 and R20 are a group represented by the following formula:
xe2x80x94(CH2)2xe2x80x94
and R21 is an amino group which may have a substituent or a protective group;
to the above production method wherein the amino group is an amino group of (S)-configuration;
to the above production method wherein R19 is a hydrogen atom, R20 is an amino-substituted cyclopropyl group (this amino group may have a substituent or a protective group) and R21 is a halogen atom;
to the above production method wherein R21 is a fluorine atom; to the above production method wherein R20 and R21 are in cis-form; and to the above production method wherein R20 is (R)-configuration and R21 is (S)-configuration.
The invention also relates to a compound represented by formula (A): 
[wherein X1 represents a hydrogen atom or a halogen atom, X2 represents a halogen atom, X3 represents a hydrogen atom or a halogen atom, R16 represents a hydrogen atom or an acyl group, R17 represents an acyl group, and R18 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a boron-containing substituent represented by the following formula:
xe2x80x94B(R5)2
(wherein R5 represents a halogen atom or an acyloxy group)], and further relates to the following related compounds.
The above compound wherein R16 is a hydrogen atom and R17 is an acyl group;
each of the above compounds wherein R17 is an acetyl group;
each of the above compounds wherein X1 and X2 are a fluorine atoms;
each of the above compounds wherein R18 is a hydrogen atom; a compound represented by formula (C-1): 
[wherein X1 represents a hydrogen atom or a halogen atom, X3 represents a hydrogen atom or a halogen atom, each of R19 and R20 independently represents a hydrogen atom, a lower alkyl group or an amino-substituted cyclopropyl group (this amino group may have a substituent or a protective group), or R19 and R20 maybe combined into a group represented by the following formula
xe2x80x94(CH2)2xe2x80x94
and form a spiro cyclic structure together with the pyrrolidine ring, and R21 represents a halogen atom or an amino group which may have a substituent or a protective group];
the above compound wherein R19 and R20 are a group represented by the following formula:
xe2x80x94(CH2)2xe2x80x94
and R21 is an amino group which may have a substituent or a protective group;
the above compound wherein the amino group is an amino group of (S)-configuration;
the above compound wherein R19 is a hydrogen atom, R20 is an amino-substituted cyclopropyl group (this amino group may have a substituent or a protective group) and R21 is a halogen atom;
the above compound wherein R21 is a fluorine atom;
the above compound wherein R20 and R21 are in cis-form;
the above compound wherein R20 is (R)-configuration and R21 is (S)-configuration;
a compound represented by formula (C-2): 
[wherein X1 represents a hydrogen atom or a halogen atom, X3 represents a hydrogen atom or a halogen atom, R16 represents a hydrogen atom or an acyl group, R17 represents an acyl group, R18 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a boron-containing substituent represented by the following formula:
xe2x80x94B(R5)2
(wherein R5 represents a halogen atom or an acyloxy group), each of R22 and R23 independently represents a hydrogen atom, a lower alkyl group or an amino-substituted cyclopropyl group (this amino group may have a substituent), or R22 and R23 may be combined into a group represented by the following formula:
xe2x80x94(CH2)2xe2x80x94
and form a spiro cyclic structure together with the pyrrolidine ring, and R23 represents a halogen atom or an amino group which may have a substituent];
the above compound wherein R22 and R23 are a group represented by the following formula:
xe2x80x94(CH2)2xe2x80x94
and R24 is an amino group which may have a substituent; the above compound wherein the amino group is an amino group of (S)-configuration;
the above compound wherein R22 is a hydrogen atom, R23 is an amino-substituted cyclopropyl group (this amino group may have a substituent) and R24 is a halogen atom;
the above compound wherein R24 is a fluorine atom;
the above compound wherein R23 and R24 are in cis-form;
the above compound wherein R23 is (R)-configuration and R24 is (S)-configuration;
the above compound wherein R16 is a hydrogen atom and R17 is an acyl group;
the above compound wherein R17 is an acetyl group;
each of the above compounds wherein X1 and X3 are fluorine atoms; and
each of the above compounds wherein R18 is a hydrogen atom.
The production method of the invention is characterized in that the following substitution reaction is carried out under a pressurized condition: 
(wherein R1, R2, R3, R4, R5, R6, R, X1, X2 and Y are as defined in the foregoing).
Firstly, substituent groups of the compound represented by the formula (1) or (2) are described.
The substituent R1 is an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms having a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxy group having from 1 to 6 carbon atoms or an alkylamino group having from 1 to 6 carbon atoms.
In this case, an ethyl group is particularly preferable as the alkyl group having from 1 to 6 carbon atoms. A vinyl group or a 1-isopropenyl group is preferable as the alkenyl group having from 2 to 6 carbon atoms. A 2-fluoroethyl group is preferable as the halogenoalkyl group having from 1 to 6 carbon atoms. A halogen atom is preferable as the substituent group of the cyclic alkyl group having a substituent, and a fluorine atom is particularly preferable as the halogen atom.
Examples of the aryl group which may have a substituent include phenyl groups which may have from 1 to 3 substituents selected from the group consisting, for example, of halogen atoms such as a fluorine atom, a chlorine atom and a bromine atom, a hydroxyl group, an amino group, a nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxy group having from 1 to 6 carbon atoms, of which a phenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-fluoro-4-hydroxyphenyl group, a 3-amino-4,6-difluorophenyl group and a 4,6-difluoro-3-methylaminophenyl group are preferable.
The heteroaryl group is a substituent derived from a five-membered or six-membered aromatic heterocyclic compound containing one or more hetero-atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. As examples of the heteroaryl group of substituent R1, a pyridyl group and a pyrimidyl group can be cited. An alkyl group and a halogen atom, for example, are preferable as the substituents on these rings. A 6-amino-3,5-difluoro-2-pyridyl group is particularly preferable.
A methoxy group is preferable as the alkoxy group having from 1 to 6 carbon atoms. A methylamino group is preferable as the alkylamino group having from 1 to 6 carbon atoms.
As the substituent R1, a halogenocycloalkyl group is preferred, and a 2-halogenocyclopropyl group is more preferred. As the halogen atom, a fluorine atom is preferable.
The substituent R2 is a hydrogen atom or an alkylthio group having from 1 to 6 carbon atoms, or R2 and R1 may be combined to form a hydrocarbon cyclic structure together with the carbon atom and nitrogen atom, to which they are bonded. The thus formed ring may contain a sulfur atom as a constituting atom, and this ring may further have an alkyl group having from 1 to 6 carbon atoms as a substituent. The ring to be formed may have a size of from four-membered ring to six-membered ring, and this ring may be in a saturated, partially saturated or unsaturated form. The following can be cited as the condensed ring structure formed in this manner. 
The substituent X1 is a hydrogen atom or a halogen atom, and a fluorine atom is preferable when it is a halogen atom. Among them, a fluorine atom or a hydrogen atom is preferable as the substituent.
The substituent R3 is a hydrogen atom, an amino group, a thiol group, a halogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms.
The alkyl group is a straight chain or branched chain group having from 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group. The alkenyl group is a straight chain or branched chain group having from 2 to 6 carbon atoms, preferably a vinyl group. The alkynyl group is a straight chain or branched chain group having from 2 to 6 carbon atoms, preferably an ethynyl group. As the halogen of halogenomethyl group, a fluorine atom is particularly preferable, and its number is from 1 to 3. As the alkoxy group, it may have from 1 to 6 carbon atoms, and an methoxy group is preferable.
The substituent R3 is preferably a hydrogen atom, an alkyl group or an amino group, of which a methyl group or an unsubstituted amino group is preferable.
When the substituent R3 is an amino group or a thiol group, it may be protected with a usually used protective group.
Examples of the protective group include a (substituted) alkoxycarbonyl group such as a tert-butoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group; a (substituted) aralkyloxycarbonyl group such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group; a (substituted) acyl group such as an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group or a benzoyl group; a (substituted) alkyl group or a (substituted) aralkyl group such as a tert-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group or a triphenylmethyl group; (substituted) ethers such as a methoxymethyl group, a tert-butoxymethyl group, a tetrahydropyranyl group and a 2,2,2-trichloroethoxymethyl group; and (alkyl and/or aralkyl)-substituted silyl groups such as a trimethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a tribenzylsilyl group and a tert-butyldiphenylsilyl group. Compounds having certain substituents protected with these substituents are particularly preferable as production intermediates (the term xe2x80x9c(substituted)xe2x80x9d as used herein means that it may have a substituent).
R4 is a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms,
wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms.
The alkyl group is a straight chain or branched chain group having from 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group. The alkenyl group is a straight chain or branched chain group having from 2 to 6 carbon atoms, preferably a vinyl group. The alkynyl group is a straight chain or branched chain group having from 2 to 6 carbon atoms, preferably an ethynyl group. As the halogen of halogenomethyl group, a fluorine atom is particularly preferable, and its number may be from 1 to 3. As the alkoxy group, it may have from 1 to 6 carbon atoms, and a methoxy group is preferable. As the halogen of halogenomethoxy group, a fluorine atom is particularly preferable, and its number may be from 1 to 3.
Among these substituents, alkyl groups or alkoxy groups are preferably. More preferred are a methyl group and an ethyl group.
In addition, this R4 and the R1 described in the foregoing may be combined to form a hydrocarbon cyclic structure together with the carbon atom and nitrogen atom, to which they are bonded, (the ring has a size of from four-membered ring to seven-membered ring, which may be in a saturated, partially saturated or unsaturated form), and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituting atom and may further have an alkyl group having from 1 to 6 carbon atoms as a substituent. The following structures can be exemplified as the condensed ring structure formed in this manner. 
Among these condensed ring systems, 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxy-10-yl group, particularly its 3-position (S)-methyl compound, is preferred.
Preferred as the combination of R3 and R4 is a case in which R3 is an amino group, a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R4 is an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, a halogenomethoxy group or a hydrogen atom.
More preferred combination is a case in which R3 is an amino group, a hydrogen atom or a methyl group and R4 is a methyl group, a methoxy group, a difluoromethoxy group or a hydrogen atom.
Particularly preferred combination is a case in which R3 is an amino group, a hydrogen atom or a methyl group and R4 is a methyl group or a methoxy group.
For these R3 and R4, a fluorine atom is preferable as X1.
When each of X1 and X2 is a halogen atom, a fluorine atom is particularly preferable as X1.
X2 is a substituent which serves as a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having from 1 to 3 carbon atoms.
Y is a group which constitutes a carboxyl group or an carboxy ester. When it is a carboxy ester, the compound is useful as a synthesis intermediate or a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthesis intermediates.
Also, the ester to be used as a prodrug is an ester which is easily hydrolyzed in vivo and thereby forms a free carboxylic acid, and its examples include oxoalkyl esters such as acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidynyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl ester.
In addition, when Y is a group having a structure represented by the following formula:
xe2x80x94B(R5)2,
R5 is a fluorine atom or an acyloxy group having from 2 to 7 carbon atoms. The acyl moiety of the acyloxy group may be either an aliphatic acyl group or an aromatic acyl group. The aliphatic acyl group is any alkylcarbonyl group. A benzoyl group can be cited as the aromatic acyl group. As the acyloxy group of R5, the use of acetyloxy group is most convenient.
The halogenocyclopropyl group of R1 is described. As the halogen atom to be substituted, a fluorine atom and a chlorine atom can be exemplified, and a fluorine atom is particularly preferable.
As the stereochemical environment of this moiety, regarding the cyclopropane ring, it is particularly preferable that the halogen atom and pyridone-carboxylic acid moiety are in cis-form. More preferred is a (1R, 2S)-2-fluorocyclopropyl group.
So-called antipode isomers exist merely in this cis-2-halogenopropyl moiety of R1, and strong antibacterial activity and high safety were found in each of them.
On the other hand, the nitrogen-containing basic compound is a compound capable of introducing a basic substituent by a substitution reaction, represented by formula Rxe2x80x94H (wherein R is a nitrogen-containing basic substituent in which a nitrogen atom is the binding region).
A compound (A) can be exemplified as a preferred example of the compound of formula (1): 
[In this formula, X1 is a hydrogen atom or a halogen atom, X2 is a halogen atom, X3 is a hydrogen atom or a halogen atom, R16 is a hydrogen atom or an acyl group, R17 is an acyl group, and R18 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a boron-containing substituent represented by the following formula
xe2x80x94B(R5)2
(wherein R5 is a halogen atom or an acyloxy group).]
The substituent R16 is a hydrogen atom or an acyl group. As the acyl group, it may be either aliphatic or aromatic and may further have an substituent group. Examples of such a substituent include a lower alkyl group and a halogen atom. Examples of the alkyl group include a methyl group, an ethyl group and a propyl group, and examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.
Examples of the acyl group include a formyl group, an acetyl group, a propanoyl group, a butyroyl group, a benzoyl group, a fluoroacetyl group, a didluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group and a trichloroacetyl group. Among them, an acetyl group or a substituted acetyl group is preferred, and an acetyl group is most preferred.
R17 is an acyl group, and this acyl group can be regarded as the same group of R16. When R16 and R17 are simultaneously acyl groups, they may be the same or different from each other.
R18 is a hydrogen atom, a lower alkyl group or a boron-containing substituent represented by the following formula:
xe2x80x94B(R5)2
(wherein R5 is a halogen atom or an acyloxy group).
When R5 is a lower alkyl group, it may be either a straight chain or a brunched chain group having from 1 to 6 carbon atoms and may further contain a cyclic moiety. Illustrative examples of the alkyl group include a methyl group, an ethyl group and an isopropyl group.
When R18 is a boron-containing substituent having the above structure, R5 is preferably a halogen atom or an acyloxy group. As the halogen atom, a fluorine atom is preferred. The acyl group may be any one of the acyl groups exemplified in R16 and R17. An acetyl group or a substituted acetyl group is preferable as the acyl group. More preferred is an acetyl group. As the boron-containing substituent, a dihalogenoboron group is preferable, and a difluoroboron group is particularly preferable.
Illustrative examples of the mother nucleus of quinolone compounds are shown below: 
The basic substituent compound (Rxe2x80x94H) to be reacted with these compounds is described.
The compound Rxe2x80x94H is represented for example by a formula (3): 
which is characterized in that R6 and R7 may be the same or different from each other and each represents an optional substituent selected from an alkyl group having from 1 to 6 carbon atoms which may be substituted by an optional substituent selected from the group (halogen, C1-6 alkyl group and C1-6 alkoxy group), an alkyl group having from 1 to 6 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group having from 7 to 12 carbon atoms, an acyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms and a hydrogen atom, wherein the cycloalkyl group, aryl group and aralkyl group may become a heterocycle containing one or more hetero-atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Its illustrative examples include amine compounds such as ethylamine, butylamine, diethylamine, isopropylamine, tert-butylamine, diisopropylamine, benzylamine, benzylmethylamine, dibenzylamine, cyclopropylamine, cyclohexylamine and aniline, and compounds in which these unsubstituted compounds are substituted with a substituent optionally selected from the above groups.
Alternatively, R6 and R7 may form a ring together with the nitrogen atom, to which they are bonded, and the formed ring is a monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic substituent,
the heterocyclic substituent may be either in saturated or unsaturated form, may further contain one or more hetero-atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and may have a bicyclo structure or a spiro cyclic structure,
and the heterocyclic substituent has a characteristic in that it may be substituted by one or more optional substituents selected from groups (1), (2) and (3).
Substituent group (1); a C6-10 aryl group, a heteroaryl group (five-membered ring or six-membered ring which may contain from 1 to 4 hetero-atoms optionally selected from N, O and S), a C7-12 aralkyl group and C6-10 heteroaralkyl group (which may contain from 1 to 4 hetero-atoms optionally selected from N, O and S).
Substituent group (2); an amino group, a C1-6 alkyl group, a C1-6 alkylamino group, a C1-6 alkylthio group, a C1-6 halogenoalkyl group and a C16 aminoalkyl group.
Substituent group (3); a halogen atom, a hydroxyl group, a carbamoyl group and a C1-6 alkoxyl group.
Regarding the substituent group (1) which may have a substituent, preferred is at least one optional substituent selected from an alkyl group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group and an acyl group, which are substituted with at least one optional substituent selected from the group A (an amino group, a halogen atom, a hydroxyl group, a carbamoyl group, a C2-6 alkyl group, a C2-6 alkoxy group, a C2-6 alkylamino group, a C2-6 alkylthio group, a thiol group, a nitro group, a cyano group, a carboxyl group, a phenyl group, a C2-6 alkoxycarbonyl group and a C2-5 acyl group) and the group B (a halogen atom, a hydroxyl group, a C1-6 alkoxy group and a C1-6 alkylthio group).
Regarding the substituent groups (2) and (3) which may have a substituent, preferred is at least one substituent selected from a C1-6 alkyl group, a C1-6 alkoxy group, a C6-10 aryl group and a heteroaryl group (five-membered ring or six-membered ring which may contain from 1 to 4 hetero-atoms optionally selected from N, O and S).
The alkyl group moiety of the substituent group (2) may have a cyclic structure.
The amino group of the substituent group A and the amino group and amino group moiety of the substituent group (2) may have, as 1 or 2 substituents, a C1-6 alkyl group (this alkyl group may have a cyclic structure) which may have one or more substituents selected from the group C (a hydroxyl group, a halogen atom, a C1-6 alkylthio group and a C1-6 alkoxy group) (when the number of alkyl group is 2, they may be the same or different from each other), and may be protected with a protective group.
More preferred is a monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic substituent in which the nitrogen atom existing in the molecule is the binding position, which is characterized in that
the nitrogen-containing heterocyclic substituent is in saturated or unsaturated form and may further contain one or more hetero-atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,
the nitrogen-containing heterocyclic substituent may also have one or more substituent selected from the group consisting of a halogen atom, an amino group, a hydroxyl group, an alkyl group having from 1 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, an aminoalkyl group having from 1 to 6 carbon atoms and an alkylamino group which has 1 or 2 alkyl groups having from 1 to 6 carbon atoms,
the alkyl group moiety of these alkyl group, halogenoalkyl group, aminoalkyl group and alkylamino group may have a cyclic structure and may have one or more substituents selected from the group consisting of a halogen atom, an alkyl group having from 1 to 6 carbon atoms and an alkoxy group having from 1 to 6 carbon atoms, and
the amino group and the amino group moiety of amino alkyl group and alkylamino group may be protected with a protective group.
Regarding the cyclic structure which is formed when xe2x80x9cthe alkyl group moiety has a cyclic structurexe2x80x9d, its examples include a case in which it binds to the nitrogen-containing heterocyclic substituent by forming a spiro cyclic structure, a case in which it becomes a cycloalkylene group, and one of its bonds binds to the nitrogen-containing heterocyclic substituent and a case in which an alkyl group binds to the nitrogen-containing heterocyclic substituent, and a spiro cyclic structure is formed on the chain or forms a cycloalkyl structure.
The following structures can be exemplified as the substituent R: 
[In the above formulae, each of R12 and R13 independently represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 6 carbon atoms or a protective group of amino group, or R12 and R13 may be combined into a polyalkylene chain having from 2 to 6 carbon atoms and form a cyclic structure by including the nitrogen atom, to which R12 and R13 are bonded,
R14 and R15 independently represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms or a hydroxyalkyl group having from 1 to 6 carbon atoms,
or R14 and R15 may be combined into a polyalkylene chain having from 2 to 6 carbon atoms and form a cyclic structure by including the carbon atom, to which R14 and R15 are bonded, Rxe2x80x3 represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 6 carbon atoms or a polyalkylene group having from 2 to 6 carbon atoms (in this case, a cyclic structure is formed by including the atom, to which Rxe2x80x3 is bonded), and
each of m and n independently represents an integer of from 1 to 4.
Examples of the protective group of amino group include a (substituted) alkoxycarbonyl group such as a tert-butoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group; a (substituted) aralkyloxycarbonyl group such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group; a (substituted) acyl group such as an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group or a benzoyl group; a (substituted) alkyl group or a (substituted) aralkyl group such as a tert-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group or a triphenylmethyl group; (substituted) ethers such as a methoxymethyl group, a tert-butoxymethyl group, a tetrahydropyranyl group and a 2,2,2-trichloroethoxymethyl group; and (alkyl and/or aralkyl)-substituted silyl groups such as a trimethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a tribenzylsilyl group and a tert-butyldiphenylsilyl group.
The following compound (B) can be cited as a preferable compound among the compound (3): 
[In this formula, each of R19 and R20 independently represents a hydrogen atom, a lower alkyl group or an amino-substituted cyclopropyl group (this amino group may have a substituent or a protective group), or R19 and R20 may be combined into a group represented by the following formula:
xe2x80x94(CH2)2xe2x80x94
and form a spiro cyclic structure together with the pyrrolidine ring, and R21 represents a halogen atom or an amino group which may have a substituent or a protective group.]
R19, R20 and R21 are substituents on the pyrrolidine ring. Among them, each of R19 and R20 is independently a hydrogen atom, a lower alkyl group or an amino-substituted cyclopropyl group (this amino group may have a substituent or a protective group), or R19 and R20 may be combined into a group represented by the following formula:
xe2x80x94(CH2)2xe2x80x94
and form a spiro cyclic structure together with the pyrrolidine ring. R21 is a halogen atom or an amino group which may have a substituent or a protective group.
When each of R19 and R20 is a lower alkyl group, it may be either a straight chain or a brunched chain group having from 1 to 6 carbon atoms and may further contain a cyclic moiety. Illustrative examples of the alkyl group include a methyl group, an ethyl group and an isopropyl group.
Each of R19 and R20 may also be an amino-substituted cyclopropyl group, namely a cyclopropyl group, in which an amino group which may have a substituent or a protective group is substituted on the cyclopropane ring.
The protective group of the amino group on the cyclopropane ring is not particularly limited, with the proviso that it is generally used in this field, and those exemplified in the foregoing may be used.
A lower alkyl group can be cited as the substituent other than protective group, and its examples include similar lower alkyl groups described in the foregoing.
Regarding substitution position of the amino group on the cyclopropyl group, on the carbon atom where cyclopropyl group binds to the 7-position of the quinolone mother nucleus can be cited, though it may be other position than this.
When R21 is a halogen atom, it is a fluorine atom or a chlorine atom. Also, when it is an amino group which may have a substituent or a protective group, these substituent and protective group can be regarded as the same case of the amino group when R19 or R20 is an amino-substituted cyclopropyl group.
Similar to the case of the R19, R20 and R21, R22, R23 and R24 are substituents on the pyrrolidine ring. Different point in the R22, R23 and R24 is that they are amino groups resulting from the elimination of protective groups from the R19, R20 and R21 or they are substituents containing the protective group-eliminated amino group, and the case of other substituents can be considered in the same manner.
The following can be cited as more preferred examples of the substituent R: 
Each step regarding the production method of the invention is described in the following in detail using a 5-amino-8-methylquinolone compound as an example.
A Step for Producing the Compound (A) [from a Compound (E)]
In this step, the amino group of the 5-position (or a corresponding position) of the quinolone skeleton is converted into an acylamino group by an acylation reaction. In this connection, the boron chelation reaction is a reaction in which a boron-containing substituent is introduced into a carboxyl group moiety, which may be an ester, at the 3-position (or a corresponding position), and the present inventors have found that these reactions can be carried out simultaneously. As an example of the starting material of these reactions, a compound of formula (E): 
(wherein X1 is a hydrogen atom or a halogen atom, X2 and X3 are each independently a halogen atom, and R25 is a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms) can be used.
An acid anhydride or an acid halide can be used as the acylation agent to be used in the acylation reaction of this step. Examples of the acid anhydride include acetic anhydride, trifluoroacetic anhydride, phenylacetic anhydride, propionic anhydride and benzoic anhydride. Examples of the acid halide include acetyl chloride, acetyl bromide, propionyl chloride and benzoic acid chloride.
The acylation agent is used in an amount of from one equivalent to large excess based on the compound (E). When an acid halide is used, it is preferable to simultaneously use tertiary amines such as triethylamine and pyridine or a nitrogen-containing heterocyclic compound (any one of aromatic, saturated and partially saturated compounds).
When the acylation reaction and boron chelating reaction are simultaneously carried out, it is preferable as an acylation agent to use an acid chloride which does not require a base, and the reactions can be carried out under the above reaction conditions.
As the boron chelating agent to be used for the boron chelating reaction, a boron compound capable of forming a boron chelate with carboxyl group or carbonyl group is used. Illustratively, boron trihalide compounds are used, and ether complexes of these trihaloboron compounds can be used suitably. For example, a boron trifluoride diethyl ether complex and a boron trifluoride tetrahydrofuran complex can be cited. Tetrafluoroboric acid as an analogous compound of trifluoroboron can also be used. By allowing them to undergo the reaction, a dihaloboron group, particularly difluoroboron group can be introduced. Tetrafluoroboric acid is particularly preferable as the agent for simultaneously carrying out both of acylation and boron chelation by the reaction in the presence of an acid anhydride.
As the boron-containing group, it may be not only a halogen-substituted boron group but also an acyloxy-substituted boron group. Introduction of the acyloxyboron group can be carried out by preparing an acyloxyboron chelating reagent in advance from boric acid and an acid anhydride and allowing it to undergo the reaction.
Amount of the boron chelating agent to be used is within the range of from 1 equivalent to 10 equivalents, preferably within the range of from 1 equivalent to 5 equivalents, based on the compound (E).
This reaction can be carried out in a solvent, and any solvent inert to the reaction can be used. Examples of the solvent include an aromatic hydrocarbon solvent such as toluene or xylene; an ester solvent such as ethyl acetate; an ether solvent such as tetrahydrofuran or diethyl ether; a ketone solvent such as acetone or methyl isobutyl ketone; a nitrile solvent such as acetonitrile; an amide solvent such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone; a sulfoxide solvent such as dimethyl sulfoxide; and a chlorine solvent such as dichloromethane or chloroform. In addition, an acylation reagent itself may be used also as the solvent. Particularly, when an acid anhydride is used as the acylation reagent, it is preferable to use it also as the solvent. The solvent may be used in an amount of from 5 to 20 volumes based on the compound (E) (e.g., at a ratio of from 5 ml to 20 ml per 1 g of the compound (E)).
The reaction temperature is within the range of from xe2x88x9230xc2x0 C. to reflux temperature of the solvent or acylation agent. Also, the reaction time is generally within the range of from 1 to 10 hours.
In this step, there are two ways of selection, namely only the acylation is carried out or the acylation and boron chelation are simultaneously carried out. When the subsequent step in which a basic substituent is introduced into the 7-position is taken into consideration, a compound obtained by simultaneously carrying out the acylation and boron chelation has superior reactivity with the basic substituent compound, so that it is preferable to carry out this reaction. In that case, difluoroboron chelation is preferable as the boron chelation due to easiness of the reaction. That is, it is preferable to carry out the reaction of an acid hydride with dihaloboron chelation agent. Illustratively, it is preferable that the amino group is acetylated by allowing acetic anhydride to react with tetrafluoroboric acid, while difluoroboron group is introduced into the carboxyl group moiety.
A Step in Which a Basic Substituent Compound (Rxe2x80x94H) is Allowed to Undergo the Reaction
In order to obtain the compound (2), a basic substituent compound
Rxe2x80x94H
(wherein R is as defined in the foregoing)
is allowed to react with the compound (1) under a high pressure in the presence or absence of a solvent. In this case, a base as an acid receptor may be added as occasion demands.
Amount of the basic substituent compound to be used in the production method of the invention is within the range of from 1 to 10 moles, preferably within the range of from 1 to 3 moles, more preferably within the range of from 1 to 1.5 moles, based on 1 mole of the quinolone compound represented by the general formula (1).
The organic solvent to be used in the production method of the invention is not particularly limited, with the proviso that it is inert to the reaction, and its examples include an aromatic hydrocarbon solvent such as toluene or xylene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran or diethyl ether, a ketone solvent such as acetone or methyl isobutyl ketone, a nitrile solvent such as acetonitrile, an amide solvent such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-2-imidazolidinone, a sulfoxide solvent such as dimethyl sulfoxide, a sulfone solvent such as sulfolane, and a chlorine solvent such as dichloromethane or chloroform, of which acetonitrile, dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide and sulfolane are preferable. In this connection, use of the solvent is not necessary in some cases, so that the presence of the reaction solvent is not essential.
Examples of the base as an acid receptor to be used as occasion demands in the production method of the invention generally include organic amines including a trialkylamine, an aryldialkylamine and an (N-substituted) heterocyclic compound, such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-5-nonene and pyridine, and inorganic bases including alkali metal or alkaline earth metal salts of carbonic acid or hydrogen carbonic acid compound, such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. Amount of the base to be used may be from the same equivalent to excess amount, but it is general to use up to approximately 3 equivalents.
The reaction of the production method of the invention is carried out at a temperature within a range of up to boiling point of the solvent to be used, with the lower limit of 0xc2x0 C. and the upper limit of 200xc2x0 C., but when a boron-chelated quinolone compound is used, the lower limit is 0xc2x0 C., preferably 40xc2x0 C., and the upper limit is 80xc2x0 C., preferably 50xc2x0 C.
Pressure during the reaction of the production method of the invention is 1xc3x97107 Pa, preferably 1.5xc3x97107 Pa, as the lower limit, and 5xc3x97108 Pa, preferably 3.5xc3x97108 Pa, as the upper limit.
The reaction under a high pressure is carried out in a reaction vessel which can sufficiently withstand such a high pressure. The following shows a series of the high pressure reaction steps.
(1) A reaction solution prepared by dissolving the material and necessary agents is transferred into a high pressure reaction vessel, and inside of the high pressure reaction vessel is heated to a predetermined temperature.
(2) After confirming that the temperature became constant, the reaction solution is directly pressurized to a predetermined pressure using a piston connected to a hydraulic pump and hydraulic cylinder.
(3) The reaction is carried out by allowing the solution to stand for a predetermined period of time while keeping the temperature, and then the reaction solution is returned to ordinary pressure and taken out.
Though the reaction time in the production method of the invention is not particularly limited, it is approximately from 3 to 24 hours, but a portion of the material remains in some cases even when the reaction is carried out in this manner. In that case, yield of the product of interest can be improved by once suspending the reaction to recover the material and then subjecting it again to the reaction. According to the method of the invention, decomposition of the material compound can be prevented so that the material compound can be recovered to a recyclable degree, which is useful.
The substitution reaction of the basic substituent compound can be carried out by the following reaction. For example, the compound (C) can be obtained by allowing the compound (A) to react with the compound (B) in the presence or absence of a base, but, in this case, pressurization may not be necessary depending on the structure of X3 and compound (B): 
The base to be used may be the same as the above case, and its examples include organic compounds such as a nitrogen-containing heterocyclic compound (aromatic, saturated or partially saturated), a tertiary amine compound and a secondary amine compound (an aromatic hydrocarbon system, an aliphatic system, an aralkyl system and a nitrogen-containing heterocyclic system can be exemplified based on the kind of substituents, and the substituents maybe either a single system or a scramble system of them). In addition to the compounds cited in the foregoing, its illustrative examples include pyridine, 4-dimethylaminopyridine, triethylamine, tributylamine, N-methylpiperidine, DBU, diisopropylamine, dibenzylamine and 2,2,6,6-tetramethylpiperidine. It may also be an inorganic base, and its examples include carbonate, hydroxide or bicarbonate of an alkali metal compound or alkaline earth metal compound, such as potassium carbonate and potassium hydroxide. Also useful as the base are sodium hydride and potassium tert-butoxide as an alkoxide.
The base may be used in an amount of from 1 to 10 equivalents based on the compound (A).
This reaction is generally carried out in a solvent, and any solvent inert to the reaction can be used. Examples of the solvent include an aromatic hydrocarbon solvent such as toluene or xylene; an ester solvent such as ethyl acetate; an ether solvent such as tetrahydrofuran or diethyl ether; a ketone solvent such as acetone or methyl isobutyl ketone; a nitrile solvent such as acetonitrile; an amide solvent such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-2-imidazolidinone; a sulfoxide solvent such as dimethyl sulfoxide; a sulfone solvent such as sulfolane; and a chlorine solvent such as dichloromethane or chloroform. Among them, acetonitrile, dimethylformamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide and sulfolane are preferable. These solvent may be used in an amount of approximately from 2 to 50 volumes based on the compound (A).
The reaction temperature is within the range of from 0xc2x0 C. to reflux temperature of the solvent to be used, preferably within the range of 30xc2x0 C. to 90xc2x0 C., but when the compound (A) is a boron-chelated compound, a range of from 30xc2x0 C. to 50xc2x0 C. is particularly preferable. Also, the reaction time is generally within the range of from 15 hours to 20 days.
A Step in Which a Compound (D) is Produced from the Compound (C)
A compound (D) can be obtained by hydrolysis reaction of the compound (C). In the hydrolysis reaction of this step, acylated amino group and boron-chelated carboxyl group are respectively converted into amino group and carboxyl group. When a protective group is present, a step for its elimination is also included. 
This reaction can be carried out under a known hydrolysis reaction condition such as an acidic condition or an alkaline condition. Examples of the acid to be used in the hydrolysis reaction under an acidic condition include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid. As the hydrolysis with acid, hydrolysis using an inorganic acid is preferable. Also, examples of the alkali to be used in the hydrolysis reaction under an alkaline condition include sodium hydroxide and potassium hydroxide.
This reaction can be carried out in an aqueous solution of the above acid or alkali but can also be carried out in an organic solvent such as methanol, ethanol or isopropanol or in a water-containing organic solvent, and the solvent is used in an amount of from 5 to 20 volumes based on the compound (C).
The reaction temperature is within the range of from 0xc2x0 C. to reflux temperature of the solvent to be used. Also, the reaction time is generally within the range of from 1 to 10 hours.
Since an amino group is present in the compound (B) used in the reaction to obtain the compound (C), when this amino group has a protective group, it is necessary to remove this protective group. Removing reaction of the protective group may be carried out at the same time with the above hydrolysis reaction when the same conditions can be used. When deprotection is carried out independently from the hydrolysis reaction, the protective group can be removed by a known method depending on the kind of used protective group. 
The compound (C-1) is a compound in which an acyl group of the amino group is removed, and the compound (C-2) is a compound in which a protective group on a substituent, particularly the protective group of amino group, is removed. Since the above deprotection reaction can be effected by stepwise removal of protective groups, these compounds can be obtained.
In addition, when R18 is an ester, it may be hydrolyzed under an acidic or basic condition. When R18 is a boron chelate, it can be converted into carboxylic acid through cleavage of the boron chelate by heat treatment in a protic solvent if necessary in the presence of a base.